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Published on: December 22, 2020
Fibulin-5 Blocks Microenvironmental ROS in Pancreatic Cancer
Miao Wang1, Mary Topalovski1, Jason E Toombs1
1Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
Abstract:
Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
Insights
Fibulin-5 (Fbln5) mutation in pancreatic cancer reduces tumor growth by increasing oxidative stress. This discovery enhances chemotherapy response and survival in pancreatic ductal adenocarcinoma (PDAC) models.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Elevated oxidative stress is characteristic of many solid tumors.
- Reactive oxygen species (ROS) homeostasis is crucial for normal cell function, but excessive ROS can cause toxicity.
- Targeting tumor-specific biochemical differences, like oxidative stress, may improve anticancer agent efficacy.
Purpose of the Study:
- To investigate the role of Fibulin-5 (Fbln5) in pancreatic ductal adenocarcinoma (PDAC) progression.
- To explore the relationship between the extracellular matrix (ECM) and ROS production in PDAC.
- To determine if modulating Fbln5 function can enhance PDAC treatment response.
Main Methods:
- Utilized genetically engineered mouse models of PDAC.
- Investigated the impact of mutating the integrin-binding domain of Fbln5.
- Conducted mechanistic studies to elucidate the role of Fbln5 in ROS production and signaling pathways.
- Assessed tumor growth, survival rates, and chemoresponse to standard PDAC therapies.
Main Results:
- Mutation of the Fbln5 integrin-binding domain led to decreased tumor growth and increased survival in PDAC models.
- Fbln5-mutant tumors exhibited higher levels of oxidative stress, contributing to improved survival.
- Loss of Fbln5-integrin interaction enhanced fibronectin signaling, promoting integrin-induced ROS production via 5-lipooxygenase.
- Fbln5 acts as a molecular rheostat, modulating cell-ECM interactions to regulate ROS production.
Conclusions:
- Fibulin-5 (Fbln5) promotes PDAC progression by reducing ROS production, favoring tumor cell survival and treatment resistance.
- Targeting the Fbln5-integrin interaction offers a potential strategy to increase oxidative stress in PDAC tumors.
- Modulating ROS levels through ECM interactions could enhance the efficacy of standard PDAC therapies.
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